Pyrimidine nucleosides are important antiviral agents, increased attention has recently been focussed on these compounds with the FDA approval of 3'-azido-2',3'-dideoxythymidine (AZT) as an effective treatment for Acquired Immunodeficiency Syndrome (AIDS). Since the synthesis of AZT utilizes the pyrimidine nucleoside .beta.-thymidine as a starting material, new methods for the low-cost production of this and other synthetic intermediates are also becoming important. The present invention involves an expeditious route to the O.sup.2,2'-anhydro-1-(.beta.-D-arabinofuranosyl)pyrimidine nucleosides, a class of compounds easily converted to the .beta.-pyrimidine derivatives. The synthesis of these anhydronucleosides is described in the following publications.
Japanese Kokai No. 81 49 398 laid open on May 2, 1981 refers to the synthesis of acylated arabinofuranosylcyclothymine compounds. The process of the Japanese Kokai requires that the iminoarabino(1 2:4.5) oxazoline acid addition salt be acylated.
In an article appearing in J. Mol. Biol. 1970, 47, 537, the authors describe the use of a readily available amino-oxazoline carbohydrate derivate as a useful precursor to a variety of anhydronucleosides.
In the reference, Kampe, K. D., Justus Leibigs Ana-Chem. 1974, (4), 593-607 (ger), reactions of aminooxazolines with unsaturated esters are disclosed. European Patent Application 0 351 126 discloses a process for the formation of O.sup.2,2'-anhydro-1-(.beta.-D-arabinofuranosyl)thymine by reacting 2-amino-.beta.-D-arabinofurano-oxazoline(s) with an alkyl 3-halo or alkoxy-methacrylate derivative.
The present invention is also directed to forming O.sup.2,2'-anhydro-1-(.beta.-D-arabinofuranosyl)pyrimidines by condensing 2-amino-.beta.-D-arabinofurano-oxazoline(s) with methyl acrylate and acrylonitrile derivatives.
Our invention differs from the prior art by starting with acrylates or acrylonitriles and related derivatives; compounds that are at a lower oxidation state than other substrates previously used for similar condensations. This results in the formation of 5,6-dihydro pyrimidine nucleoside derivatives which are then oxidized to the required nucleosides in high to excellent yields.
Broadly, the present invention is directed to a process for the production of pyrimidine nucleoside compounds of the formula: ##STR4## wherein R.sub.1 and R.sub.2, each are alkyl C.sub.1 -C.sub.16, substituted alkyl, aryl, substituted aryl, aralkyl, substituted aralkyls, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cyano, carboxy, carboxy esters, carboxamido, N-mono substituted and N,N-disubstituted carboxamido with alkyl, aralkyl, and aryl groups. R.sub.3 is hydrogen or OR.sub.4 ; R.sub.4 is hydrogen, triphenylmethyl, or silyl which is substituted by three substituents selected from C.sub.1 -C.sub.6 alkyl, phenyl, or combinations thereof; and X=O or NH: comprising condensing a compound of the formula: ##STR5## wherein R.sub.3 and R.sub.4 are as defined above with a compound of either the formula: ##STR6## R.sub.1 and R.sub.2 are as defined above; and R.sub.5 is C.sub.1 -C.sub.4 alkyl.
The condensation is in the presence of a reaction inert solvent at a temperature of 50.degree. C. to about 150.degree. C.; to form a compound of the formula: ##STR7## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 and X are as defined above.
A compound of the formula IV is oxidized to form the compound of formula I.
The present invention is also directed to compounds of formula IV.